GUTMOM
Maternal obesity and cognitive dysfunction in the offspring: cause-effect role of the GUT MicrobiOMe and early dietary prevention
Early life is fundamental for brain and microbiota development. Gut microbiota influences brain function. Maternal obesity affects maturation of gut microbiota and is an important predictor of cognitive dysfunction in the offspring. Cognitive decline through life is an increasingly invalidating condition, due to population ageing and the high frequency of predisposing factors (obesity, unhealthy diets). We hypothesized that the negative effects of maternal obesity on cognitive function in the offspring are partly mediated by the microbiota and its metabolites, offering the opportunity for non-invasive risk-screening and -reduction by tailored foods and diets, since earliest life stages. We used two existing cohorts of children to provide leads, and preclinical models to prove cause-effect relationships, and develop tailored dietary interventions to counteract the effects of maternal obesity on cognition. GUTMOM involved academic centres, and a private industrial collaborator providing project co-funding. Our results indicate that maternal high-fat diet (HFD) and early-life stress (ELS) were more impactful than maternal body weight on offspring's health in mice; we identified bacteria and fecal metabolites that predicted cognition in children, and showed that fecal transplantation into mice reproduced a correlated phenotype. We also showed that ELS has an important impact on fecal microbiota and metabolites, with gender differences, and that antioxidant treatment during pregnancy is more beneficial for brain BDNF and CD68 expression in female than male mice born to HFD dams. The plan included intensive dissemination and training activities for young scientists, and the study has contributed to the ongoing Knowledge Platform on Diet, Intestinal Microbiomics and Health.
Consortium
Partner Organization | Partner Country |
---|---|
University of Valencia | Spain |
Radboud UMC | Netherlands |
Max Planck Gesellschaft (MPG) | German |
Istituto Superiore di Sanità (ISS) (Collaborator in-kind) | Italy |
Mead Johnson Nutrition (now RB) (Collaborator in-kind and in cash) | Netherlands |
Highlights
Results indicate:
- a positive effect of breastfeeding (in girls) or prescholar adherence to a mediterranean diet on selected neurodevelopment domains;
- maternal BMI effects on microbiota and neurodevelpment in early childhood, but mice and human studies suggest that HFD during pregnancy is more impactful in adulthood than maternal BMI, and
- a predictive value of meconium bacteria on prescholar neurodevelopment, and 4) of selected fecal metabolites (also related with exclusive breast-feeding), as measured contextual to cognitive function at precholar age;
- the transfer of prescholar children-donors' phenotype into recipient germ-free mice, via microbiota transplantation;
- an impact of maternal HFD, ELS and the combination on offspring's body weight, especially in males, and
- a strong impact of ELS on microbiota, especially in females, and fecal metabolome, especially in males, as well as on the microbiota-metabolome association;
- efficacy of prenatal (maternal) administration of the antioxidant N-acetyl-cysteine (NAC) to prevent the negative effects of maternal HFD, by buffering adverse changes in brain BDNF and CD68 expression in female mice.
Products
Author: Forsgård RA, Marrachelli VG*, Lindén J, Frias R, Collado MC*, Korpela R, Monleon D*, Spillmann T, Österlund P.
Link: https://doi.org/10.1016/j.tranon.2019.04.019
Author: Gómez-Gallego C, Morales JM*, Monleón D*, du Toit E, Kumar H, Linderborg KM, Zhang Y, Yang B, Isolauri E, Salminen S, Collado MC.
Link: https://doi.org/10.3390/nu10101355
Author: Viña J*, Borras C*, Gomez-Cabrera MC*.
Link: https://doi.org/10.1016/j.freeradbiomed.2018.06.028
Author: Inglés M*, Mas-Bargues C*, Berna-Erro A*, Matheu A*, Sanchís P*, Avellana JA*, Borrás C*, Viña J*.
Link: https://doi.org/10.1093/gerona/gly168
Author: Díaz A*, López-Grueso R*, Gambini J*, Monleón D*, Mas-Bargues C*, Abdelaziz KM*, Viña J*, Borrás C*.
Link: https://doi.org/10.1155/2019/6734836
Author: Inglés M*, Mas-Bargues C*, Gimeno-Mallench L*, Cruz-Guerrero R, García-García FJ, Gambini J*, Borrás C*, Rodríguez-Mañas L, Viña J*.
Link: https://doi.org/10.1016/j.jamda.2019.03.011
Author: Mas-Bargues C*, Sanz-Ros J*, Román-Domínguez A*, Inglés M*, Gimeno-Mallench L*, El Alami M*, Viña-Almunia J*, Gambini J*, Viña J*, Borrás C*.
Link: https://doi.org/10.3390/ijms20051195
Author: Pamplona R, Borras C*, Jové M, Pradas I, Ferrer I, Viña J*.
Link: https://doi.org/10.1016/j.freeradbiomed.2019.03.016
Author: Häusl AS*, Balsevich G*, Gassen NC*, Schmidt MV*.
Link: https://doi.org/10.1016/j.molmet.2019.09.003
Author: Balsevich G, Abizaid A, Chen A, Karatsoreos IN, Schmidt MV*.
Link: https://doi.org/10.1016/j.ynstr.2019.100171
Author: Iozzo P*, Guzzardi MA*
Link: https://doi.org/10.1530/ec-19-0348
Author: Sanguinetti E*, Guzzardi MA*, Tripodi M*, Panetta D*, Selma-Royo M, Zega A*, Telleschi M*, Collado MC, Iozzo P*.
Link: https://doi.org/10.1038/s41598-019-48090-8
Author: Cirulli F*, Musillo C*, Berry A*.
Link: https://doi.org/10.1016/j.neuroscience.2020.01.023
Author: Cirulli F*
Link: https://doi.org/10.1016/B978-0-12-819262-7.00009-X
Author: Perez-Terol I*, Rios-Navarro C*, de Dios E*, Morales JM*, Gavara J*, Perez-Sole N*, Diaz A*, Minana G*, Segura-Sabater R*, Bonanad C*, Bayés-Genis A*, Husser O, Monmeneu JV*, Lopez-Lereu MP*, Nunez J*, Chorro FJ*, Ruiz-Sauri A*, Bodi V*, Monleon D*.
Link: https://doi.org/10.1038/s41598-019-56436-5
Author: Muñoz-Hidalgo L*, San-Miguel T*, Megías J*, Monleón D*, Navarro L*, Roldán P*, Cerdá-Nicolás M*, López-Ginés C*.
Link: https://doi.org/10.1016/j.neo.2019.09.001
Author: Borrás C*, Mas-Bargues C*, Román-Domínguez A*, Sanz-Ros J*, Gimeno-Mallench L*, Inglés M*, Gambini J*, Viña J*.
Link: https://doi.org/10.3390/ijms21020418https://doi.org/10.3390/ijms21020418
Author: Borras C*, Ingles M*, Mas-Bargues C*, Dromant M*, Sanz-Ros J*, Román-Domínguez A*, Gimeno-Mallench L*, Gambini J*, Viña J*.
Link: https://doi.org/10.1016/j.mad.2019.111199
Author: Borras C*, Mas-Bargues C*, Sanz-Ros J*, Román-Domínguez A*, Gimeno-Mallench L*, Inglés M*, Gambini J*, Viña J*.
Link: https://doi.org/10.1016/j.freeradbiomed.2019.11.032
Author: Guzzardi MA*, Granziera F*, Sanguinetti E*, Muratori F, Iozzo P*.
Link: https://doi.org/10.3390/nu12082320
Author: Berry A*, Mazzelli M, Musillo C*, Riva MA, Cattaneo A, Cirulli F*.
Link: https://doi.org/10.1111/ejn.15181
Author: Gambini J*, Gimeno-Mallench L*, Olaso-Gonzalez G*, Mastaloudis A, Traber MG, Monleón D*, Borrás C*, Viña J*.
Link: https://doi.org/10.3390/antiox10020301
Author: Muñoz-Hidalgo L*, San-Miguel T*, Megías J*, Serna E*, Calabuig-Fariñas S*, Monleón D*, Gil-Benso R*, Cerdá-Nicolás M*, López-Ginés C*.
Link: https://doi.org/10.3390/ijms22010368
Author: Mas-Bargues C*, Borrás C*.
Link: https://doi.org/10.1016/j.freeradbiomed.2021.03.028
Author: Duro-Castano A*, Borrás C*, Herranz-Pérez V*, Blanco-Gandía MC, Conejos-Sánchez I*, Armiñán A*, Mas-Bargues C*, Inglés M*, Miñarro J*, Rodríguez-Arias M*, García- Verdugo JM*, Viña J*, Vicent MJ.
Link: https://doi.org/10.1126/sciadv.abf9180
Author: Mas-Bargues C*, Borrás C*, Viña J*.
Link: https://doi.org/10.3390/ijms22041527
Author: Mota-Martorell N, Jové M, Borrás C*, Berdún R, Obis È, Sol J, Cabré R, Pradas I, Galo-Licona JD, Puig J, Viña J*, Pamplona R.
Link: https://doi.org/10.1016/j.freeradbiomed.2020.11.026
Author: Marinelli R, Torquato P, Bartolini D, Mas-Bargues C*, Bellezza G, Gioiello A, Borras C*, De Luca A, Fallarino F, Sebastiani B, Mani S, Sidoni A, Viña J*, Leri M, Bucciantini M, Nardiello P, Casamenti F, Galli F.
Link: https://doi.org/10.1074/jbc.ra120.013303
Author: Mas-Bargues C*, Sanz-Ros J*, Román-Domínguez A*, Gimeno-Mallench L*, Inglés M*, Viña J*, Borrás C*.
Link: https://doi.org/10.3390/biom10060957
Author: Borras C*, Delaunay K, Slaoui Y, Abache T, Jorieux S, Naud MC, Sanharawi ME, Gelize E, Lassiaz P, An N, Kowalczuk L, Ayassami C, Moulin A, Behar-Cohen F, Mascarelli F, Dinet V.
Link: https://doi.org/10.3389/fimmu.2020.00443
Author: Borras C*, Canonica J, Jorieux S, Abache T, El Sanharawi M, Klein C, Delaunay K, Jonet L, Salvodelli M, Naud MC, Arsenijevic Y, Shalabi A, Souchaud L, Behar- Cohen F, Dinet V.
Link: https://doi.org/10.1038/s41598-019-50420-9
Author: Pradas I, Jové M, Huynh K, Puig J, Ingles M*, Borras C*, Viña J*, Meikle PJ, Pamplona R.
Link: https://doi.org/10.1016/j.redox.2019.101127
Author: López-Ginés C*, Muñoz-Hidalgo L*, San-Miguel T*, Megías J*, Triviño JC*, Calabuig S*, Roldán P*, Cerdá-Nicolás M*, Monleón D*.
Link: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8640814/
Author: Borrás C*, Abdelaziz KM*, Díaz A*, Gambini J*, Jové M, López-Grueso R*, Mas-Bargues C*, Monleón D*, Pamplona R, Viña J*.
Link: https://doi.org/10.1016/j.mad.2021.111596
Author: Delgado-Velandia M, Gonzalez-Marrachelli V*, Domingo-Relloso A*, Galvez-Fernandez M, Grau-Perez M*, Olmedo P*, Galan I, Rodriguez-Artalejo F, Amigo N, Briongos-Figuero L, Redon J*, Martin-Escudero JC, Monleon-Salvado D*, Tellez-Plaza M*, Sotos-Prieto M.
Link: https://doi.org/10.1186/s12966-021-01219-3
Author: Mas-Bargues C*, Alique M, Barrús-Ortiz MT, Borrás C*, Rodrigues-Díez R.
Link: https://doi.org/10.3390/antiox11010078
Author: Mirón Mombiela R*, Vucetic J*, Monllor P*, Cárdenas-Herrán JS*, Taltavull de La Paz P, Borrás C*.
Link: https://doi.org/10.1177/01617346211029656
Author: Borrás C*, Ferrando M, Inglés M*, Gambini J*, Lopez-Grueso R*, Edo R*, Mas-Bargues C*, Pellicer A*, Viña J*.
Link: https://doi.org/10.1155/2021/8101615
Author: Guzzardi MA*, La Rosa F*, Campani D, Cacciato Insilla A, De Sena V*, Panetta D*, Brunetto MR, Bonino F, Collado MC, Iozzo P*.
Link: https://doi.org/10.3390/nu13103438
Author: Pinart M, Nimptsch K, Forslund SK, Schlicht K, Gueimonde M, Brigidi P, Turroni S, Ahrens W, Hebestreit A, Wolters M, Dötsch A, Nöthlings U, Oluwagbemigun K, Cuadrat RRC, Schulze MB, Standl M, Schloter M, De Angelis M, Iozzo P*, Guzzardi MA*, Vlaemynck G, Penders J, Jonkers DMAE, Stemmer M, Chiesa G, Cavalieri D, De Filippo C, Ercolini D, De Filippis F, Ribet D, Achamrah N, Tavolacci MP, Déchelotte P, Bouwman J, Laudes M, Pischon T.
Link: https://doi.org/10.3390/nu13093292
Author: Granziera F*, Guzzardi MA*, Iozzo P*.
Link: https://doi.org/10.3390/nu13113723
Author: Guzzardi MA*, Ederveen THA*, Rizzo F, Weisz A, Collado MC, Muratori F, Gross G*, Alkema W*, Iozzo P*.
Link: https://doi.org/10.1016/j.bbi.2021.12.009
Author: Guzzardi MA*, La Rosa F*, Campani D, Cacciato Insilla A, Nannipieri M, Brunetto MR, Bonino F, Iozzo P*.
Link: https://doi.org/10.3390/ijms23052659
Author: Guzzardi MA*, La Rosa F*, Campani D, Collado MC, Monleon D, Cacciato Insilla A, Tripodi M, Zega A*, Dattilo A, Brunetto MR, Maffei M, Bonino F, Iozzo P*.
Link: https://doi.org/10.3390/metabo12040278
Author: Berry A*, Collacchi B, Masella R, Varì R, Cirulli F*.
Link: https://doi.org/10.3390/nu13051519
Communication & Dissemination Activities
Target group | Authors | Means of communication |
---|---|---|
Scientists, clinicians, diabetologists, industry | Project partner CNR: “Neuroimaging and neuromodulation in obesity and type 2 diabetes”, Annual Meeting of the American Diabetes Association, Orlando, USA, 2018 | Invited lecture |
General practitioners, specialists | Project partner CNR: “Microbiota, health and obesity”, Medical complications of gut dysbiosis (educational event with credits), Lucca, Italy, 2018 | Plenary lecture |
PhD students, young post-doc investigators, academic scientists (approximately 30 attendants) | Project partner CNR: “Insulin sensitivity by PET imaging”, Turku Lifespan seminars, Turku, Finland, 29th April 2019 | Invited seminar |
Academic scientists (approximately 50 attendants) | Project partner CNR: “Brain metabolism in Obesity, diabetes, cognitive dysfunction. Genetic models & translational approach”, Neuroendocrinology and Brain Imaging meeting (satellite symposium of the Human Brain Mapping project), Rome, 8-9 June 2019 | Invited lecture |
Academic scientists (approximately 300 attendants) | Project partner CNR: “Cognitive decline: new evidence” as part of MULTIDISCIPLINARY AND MULTIDIMENSIONAL PANORAMA DIABETES FORUM, Italian Society of Diabetology (SID), Riccione, 8-12 March 2019 | Invited lecture |
Academic, scientist, policy makers, journalists, industry, schools (approximately 300 attendants) | Project partner CNR: “Obesity: early onset and long-term complications”, IFC50, Pisa 4 April 2019. Event created in order to celebrate 50 years of the Institute of Clinical Physiology of CNR | Invited lecture |
Academic, scientist (approximately 50 attendants) | Project partner CNR: “Organ metabolism in the obesity pathogenesis and its complications”, in the context of the XII edition of Parma Diabetes, Parma, 23-24 January 2020 | Lecture. Young Investigators Award in diabetology established by the Italian Society of Diabetology (SID) |
Academic scientists, students | Project partner MPG, University of Darmstadt, Darmstadt (Germany), May 2019 | Invited presentation |
Academic scientists, students | Project partner MPG, University of Ulm, Ulm, Germany, June 2019 | Invited presentation |
Academic scientists, students | Project partner MPG, Neuroscience School of Advanced Studies, Venice, Italy, Sept. 2019 | Invited lecturer |
Academic scientists, students | Project partner MPG, World Association of Stress and Anxiety Disorders (WASAD), Würzburg, Germany, Oct. 2019 | Plenary lecture |
Academic scientists, diabetologists, students | Project Partner CNR: “Intestino e SNC” (Gut and CNS), session “Diabetes: a central nervous system disease”, Incontri Pisani di Endocrinologia e metabolismo (IPEM) - attualità in ambito diabetologico, remote conference with ECM, 13-14 november 2020 | Invited lecture |
Scientists, academia, students, industry, clinicians | CNR. Investigation of metabolism by PET-CT, Symposium of the Study Group DiabImage, Annual Congress of the European Association for the Study of Diabetes, Virtual EASD Meeting, 28/09/2021 | Invited lecture |
Scientists, academia, obesity clinicians, nutritionists | CNR. Associations between the Mediterranean Diet Pattern and Weight Status and Cognitive Development in Preschool Children. Congress, Italian Obesity Society, Livorno 28-10-2021 | Poster, winner best session poster |
Scientists, industry, academia, students | CNR. Non-alcoholic fatty liver: brain and entero-hormones. European Association for the Study of the Liver (EASL), Dublin, scheduled for September 2022 | Invited lecture |
Academia, clinicians, students, industry | CNR. Obesity and brain. Congress of the Italian Society of Internal Medicine, Rome, scheduled for October 2022 | Invited lecture |
Academia, clinicians, students, industry | CNR. Imaging of cardiac metabolism. Italian Diabetes Society, Rimini, scheduled for October 2022 | Invited lecture |